Bronchial Hyperresponsiveness in Asthmatic Adults – a Long-Term Correlation Study

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European Review for Medical and Pharmacological Sciences 2005; 9: 125-131 Bronchial hyperresponsiveness in asthmatic adults – A long-term correlation study

R. CARBONE, F. LUPPI*, A. MONSELISE**, G. BOTTINO

Department of Internal Medicine (DIMI), University of Genoa – Genoa (Italy) *Department of Respiratory Diseases of Modena University – Modena (Italy) **Department of Internal Medicine B, Rabin Medical Center, Tel Aviv University – Tel Aviv (Israel)

Abstract. – Background: Bronchial hyper Conclusions: Although the clinical picture im- responsiveness (BHR), is a risk factor for asth- proved with therapy, BHR was not significantly ma. It is a state in which excessive narrowing of affected in any patient group, at two and five the airways occurs in response to varying stim- years of follow-up. Furthermore, no correlation uli. BHR seems to be due to the interaction of was found between the clinical picture and PD20 multiple factors and its relation to asthma is FEV1 values. BHR seems to result from the inter- complex. Asthma without BHR is unusual. In- action of multiple factors that are worth further deed, patients who show a higher degree of investigating. BHR cannot be considered a mark- symptoms have higher levels of BHR. To date no er of disease activity in asthma and therefore is study has investigated the correlation between not a useful tool for guiding asthma therapy. BHR in mild persistent asthmatic adults and a Key Words: long-term therapy of five years. The aim of this study is to evaluate (i) the role of BHR in the Bronchial hyperresponsiveness, Asthma, Therapy. clinical evaluation of asthma, (ii) the correlation between BHR and therapy in asthma. Methods: Seventy patients (were recruited 34 men, age 21-55 years) suffering from: (a) mild seasonal allergic asthma (17/70), (b) mild perennial allergic asthma (34/70) and (c) mild non-allergic asthma (19/70). 14 patients from group (a) Introduction and 28 patients from group (b) were treated with β inhaled 2-agonists, beclomethasone, disodium- Bronchial hyperresponsiveness (BHR) is a cromoglycate and immunotherapy. 14 patients state in which excessive narrowing of the air- from group (c) underwent the same treatment ways occurs in response to varying stimuli1,2. regimen without immunotherapy. All patients BHR seems to result from the interaction of were evaluated with a metacholine challenge many factors that act sometimes in synergy test. The BHR (PD20 FEV1) was calculated at 3 baseline and after a two-year symptom free peri- but may also contrast each other . The degree od. Fifteen pts were followed-up for five years of airway responsiveness has been reported with an evaluation every year. All other patients to correlate with the severity of asthma symp- did not receive any treatment. The results (ex- toms (wheeze, cough, chest tightness) and pressed as mean ± SE) were evaluated. medication requirements in both adults4 and Results: Fourteen pts and three pts from children5,6. The concept that the level of air- group (a) showed a mean BHR value of 984 ± 3.66 and 674 ± 2.06; 343 ± 7.60 and 208 ± 7.70 re- way responsiveness correlates with disease spectively. The results were not statistically sig- severity has important implications when one nificant Twenty-eight and six pts from group (b) considers stimuli that can make an individual showed mean values of 685 ± 1.45 and 1405 ± more responsive and their disease more se- 5.65; 856 ± 7.09 and 435 ± 2.20 with apparent im- vere7. BHR is not specific for asthma, it has provement for the former. Five pts and fourteen also been proposed in chronic obstructive pts from group (c) showed mean value of 2682 ± pulmonary disease (COPD). The mechanism, 7.85 and 2099 ± 6.82; 816 ± 2.53 and 877 ± 4.78 respectively. As for the 5-yr follow up ten pts which stands behind BHR, is unknown in and five pts from group (b) showed mean values asthma as well as in respiratory tract infec- of 705 ± 1.6 and 861 ± 7.15; 911 ± 7.3 and 457 ± tions, interstitial lung diseases, and other res- 2.3 respectively. piratory diseases etc.

125 R. Carbone, F. Luppi , A. Monselise, G. Bottino

There are many probable explanations for asthma according to the GINA guidelines1,10 the development and persistence of height- and with a resting FEV1 > 80 of the predicted ened bronchial responsiveness but none, at value. All patients were non-smokers at the present, are totally convincing1,8. Airway in- time of recruitment (> 1 yr; < 6 pack-yr.) and flammatory response has been proved to be were atopic 51/70. Atopy was defined as the an important trigger to BHR. This finding is presence of a positive skin test reaction to substantiated on the one hand by the correla- one or more common aeroallergens11. Subject tion of airway markers of inflammation, with characteristics are shown in Table I. The BHR, and on the other by the fact that treat- study design was a single center prospective ment aimed at reducing airway inflammation randomised trial with a 2-yr follow-up of 70 brings to a reduction of BHR and symptoms. pts and 5-yr follow-up of 15/70 pts. It took However, the relationship between airway in- place in the outpatients clinic of the Depart- flammation and BHR is complex. Some in- ment of Internal Medicine in the Genoa Uni- vestigations have shown that anti-inflamma- versity in collaboration with the Department tory therapy reduced BHR, but did not eradi- of Respiratory Diseases of the Modena Uni- cate it. A small study showed that controlling versity. airway inflammation did not reduce BHR9. Patients were divided according to the fol- To date no study has investigated the cor- lowing subsets: (a) mild seasonal allergic relation between BHR in mild persistent asthma (17/70), (b) mild perennial allergic asthmatic adults and long-term therapy of asthma (34/70), and (c) non-allergic mild five years. AIM of the study was to evaluate asthma (19/70). Among patients with mild (i) the role of BHR in the clinical evaluation seasonal allergic asthma (a) 14/17 followed an of asthma, (ii) the correlation between BHR adequate treatment regimen with an inhaled and therapy in asthma. The existence of such steroid (beclomethasone dipropionate, 3 × β a relationship may improve the understand- 200 µg/d) in addition to inhaled 2-agonists ing of the pathogenesis of BHR also in (salbutamol, 3 × 100 µg/d), sodium cromogly- bronchial asthma. cate (10 µg per day) and immunotherapy. Among patients affected with mild perennial allergic asthma (b), 28/34 patients followed the same treatment regimen as group (a). Methods 14/19 patients with non-allergic mild asthma (c) received the same therapy as that given 70 patients were recruited (34 males age for groups (a) and (b) with the exception of 21-55 years), all affected with mild persistent immunotherapy.

Table I. Population: demographics and clinical characteristics.

2-yr follow-up 5-yr follow-up

Total Treated Non-treated Total Treated Non-treated

N° patients 70 56 14 15 10 5

Mean age 38 ± 17 Range, yr. 21-55 Males 34 Females 36 Atopy 51

Seasonal mild allergic asthma 17 14 3

Perennial mild allergic asthma 34 28 6 15 10 5

Non-allergic mild asthma 19 14 5

126 Bronchial hyperresponsiveness in asthmatic adults - A long-term correlation study

Patients were excluded from the study if inhaled metacholine are said to have in- they had an asthma exacerbation requiring creased airway responsiveness. The meta- hospitalisation or a respiratory tract infec- choline PD20 was obtained from the dose-re- tion, 3 months and 4 weeks prior to beginning sponse curve plotted on a semi logarithmic of the study respectively. computerised scale in association with the 13 Patients did not receive either inhaled cor- PD20% FEV1 . β ticosteroids, long-acting 2-agonists, nor oral All the pts gave their informed consent to β 2-agonists, or any other therapy four days this study, which was approved by the Ethic prior to undergoing the PD20% FEV1 test. Committee of the University of Genoa. All patients were evaluated with a metacholine challenge test. The BHR (PD20 FEV1) was calculated at baseline and after a Data Analysis two-year symptom free period. Fifteen pts Data were analyzed using the Statistical were followed-up for five years with an ex- Analysis System package for mainframe; 14 amination at yearly intervals. Vmax 22 lv Sen- SAS; Cary NC software . Values for contin- sor Medics, Yorba Linda CA performs pul- uous variables are expressed as the mean ± monary functional tests (PFTs). PFTs were SE. Metacholine PD20 was transformed to a measured according to the American Tho- logarithmic scale for statistical calculations racic Society recommendations12. Meta- and expressed as mean ± SE. Student’s t test choline chloride was administered through an was used to compare BHR between sub- aerosol dosimeter (Mefar MB3; Bovezzo, jects. The level of statistical significance was Italy). Each subject inhaled five inspirations set at p < 0.05. of buffered saline solution (pH 7.4) and was included in the study if FEV1 after inhaling the solution was at least 80% of the predicted value. The best of three FEV1 measurements (performed 1 min after administration of Results each solution) not varying by > 5% was performed. Next, patients inhaled metacholine, The correlation between PD20% FEV1 at starting at a dose of 90 µg with escalating dos- baseline and at two years of follow-up is es according to the cumulative technique (90, shown in Table II: among patients affected 270, 540, 990, 1865, 4565, 9065, 13565 µg) un- with seasonal asthma 14/17 were treated. til an adequate response was monitored. The Mean values of BHR (PD20 FEV1) at base- test was terminated when the patient’s FEV1 line and after two years were 984 ± 3.66 and decreases by 20% of its initial value. The 674 ± 2.06 for those who were treated and, dose at which the drop in FEV1 occurs is and 343 ± 7.60 and 208 ± 7.70 for those who called the provocative dose, PD20 FEV1. Indi- did not receive therapy, respectively. P val- viduals that manifest a PD20 at a low dose of ues were not significant. The correlation be-

Table II. Seasonal allergic asthma: correlation between PD20% FEV1 at baseline and after two years of follow-up. Treated vs. non-treated pts.

Seasonal allergic asthma, treated pts X SE T df p

PD % baseline 984 3.66 20 0.77 13 0.45 PD20% after two years 674 2.06

Seasonal allergic asthma, non-treated pts X SE T df p

PD % baseline 343 7.60 20 2.32 2 0.14 PD20% after two years 208 7.70

127 R. Carbone, F. Luppi , A. Monselise, G. Bottino

Table III. Perennial asthma: correlation between PD20% FEV1 at baseline and after two years of follow-up. Treated vs. non-treated pts – no statistical significant variations in PD20% FEV1.

Perennial allergic asthma, treated pts X SE T df p

PD % baseline 685 1.45 20 1.26 27 0.21 PD20% after two years 1405 5.65

Perennial allergic asthma, non-treated pts X SE T df p

PD % baseline 856 7.09 20 84 5 0.43 PD20% after two years 435 2.20

tween PD20% FEV1 at baseline and at two Discussion years of follow-up for patients affected with perennial asthma is shown in Table III: 28/34 We hereby describe for the first time in the pts were treated. Mean values were 685 ± literature, a long term follow-up study ran- 1.45, 1405 ± 5.65 and 856 ± 7.09, 435 ± 2.20 domised that correlates BHR and therapy in for those who were treated and those who 70 adults suffering from mild persistent asth- did not receive any therapy respectively, ma. Fifteen patients out of 70 were followed with apparent improvement for the former. for five years with yearly evaluations while Table IV shows the correlation between the rest were followed for two years. Josephs 15 PD20% FEV1 at baseline and after two years et al studied a group of 20 pts affected with of follow-up for non-allergic asthmatic pts. asthma during a follow up period of 12 and Five pts of the nineteen in this subset were 18 months. Pts were of varying age and sever- non- treated. Mean values were 816 ± 2.53, ity of symptoms and were evaluated with 877 ± 4.78, and 2682 ± 7.85, 2099 ± 6.82 re- metacholine challenges. They concluded that spectively. Table V shows the analysis of the the relationship of bronchial reactivity to the data at yearly intervals during 5 years of fol- clinical state of asthma is not sufficiently low up of 15 pts affected with mild perennial close to be of practical clinical use. Orefice et allergic asthma (subset b) confirmed the re- al16 conducted a 12-week comparative study sults that no significant variation in PD20% of 165 pts. asthmatic who received randomly FEV1 was obtained with therapy. Five pts of nedocromil sodium cromoglycate and be- fifteen in this subset were non- treated. clomethasone dipropionate. No significant Mean values were 705 ± 1.6 and 861 ± 7.15 difference in PD FEV1 was noted among the respectively and 911 ± 7.3 and 457 ± 2.3. treatments.

Table IV. Non-allergic asthma: correlation between PD20% FEV1 at baseline and after two years of follow-up. Treat- ed vs. non-treated pts.

Non-allergic asthma, treated pts X SE T df p

PD % baseline 2682 7.85 20 0.11 13 0.91 PD20% after two years 2099 6.82

Non-allergic asthma, non-treated pts X SE T df p

PD % baseline 816 2.53 20 0.60 4 0.58 PD20% after two years 877 4.78

128 Bronchial hyperresponsiveness in asthmatic adults - A long-term correlation study

Table V. Perennial asthma: correlation between PD20% FEV1 at baseline and five years of follow-up. Treated vs. non- treated pts - no statistical significant variations in PD20% FEV1.

Perennial-allergic asthma, treated pts X SE T df p

PD % baseline 705 1.6 20 0.5 9 0.32 PD20% after two years 911 7.3

Perennial-allergic asthma, non-treated pts X SE T df p

PD % baseline 861 7.15 20 0.7 4 0.38 PD20% after two years 457 2.3

Despite the fact that BHR has been stud- tract infections, air pollution and occupational ied intensely its role in the evaluation of agents. Different therapies aimed at decreasing asthmatic pts is still a controversial issue. BHR (but not eliminating it) are described in Some deem it an essential test while others the literature: (a) avoiding contact with specific consider it relatively useless. The question allergens, (b) pharmacotherapy, i.e. glucocorti- that arouses is whether the test has any role coids (parental and inhaled), sodium cromo- in symptomatic pts whose diagnosis is more glycate, (c) allergen immunotherapy. Inhala- ambiguous. The positive predictive value of tion of glucocorticoids appears to be the most the test is compromised by the prevalence of effective therapy to reduce BHR. Inhaled glu- asymptomatic individuals with bronchial hy- cocorticoids have been proven to be more ef- perresponsiveness in the general population. fective than oral steroids. Multiple studies in Although it’s negative predictive value is still children and adults show significant improve- a matter of debate, a few studies have shown ments in BHR with long-term administration that asthma in the absence of bronchial hy- of inhaled glucocorticoids. perresponsiveness is very unusual and that Sont et al17 conducted the first long-term therefore a negative test can rule out the dis- randomised follow up study (2 yr. follow-up) ease. The aim of our study was to evaluate in which they evaluated airway hyperrespon- (i) the role of BHR in the clinical assessment siveness as an additional guide to long-term of asthma, (ii) the correlation between BHR treatment and concluded that monitoring and therapy in-patients affected with asthma. BHR could be a useful tool in the evaluation The responsiveness to metacholine did not of disease activity. correlate in general with the severity of After a 5 yr. of follow-up, we have demon- symptoms although patients with severe strated that therapy with beclomethasone β symptoms tend to be more responsive to the dipropionate, 2-agonists, and sodium cromo- test. Interestingly few exacerbations were glycate in pts of subsets (a) and (b), and with- observed in the absence of apparent out the addition of immunotherapy in subset bronchial hyperresponsiveness, which may (c), resulted in an improvement of both clini- indicate that the latter is not a necessary ele- cal and functional parameters. A reduction of ment in asthma. Indeed, evaluating BHR relapses was noted in all pts. may be a more reliable diagnostic tool in se- According to the current guidelines be- verely affected pts. clomethasone dipropionate and budesonide The relationship between BHR and asthma have equal efficacy in asthma and are recom- is complex and is modulated by many factors. mended at similar doses18. A meta-analysis of BHR is dynamic and influenced by different 42 studies (> 10.000 pts) including children stimuli most of which are environmental and and adults which compared fluticasone to be- that appear to induce airway inflammation. clomethasone or budesonide in asthma con- Among environmental factors that increase cluded that fluticasone given at half the daily BHR it is noteworthy mentioning allergens dose of beclomethasone and budesonide (natural and experimental), viral respiratory brings to only a small clinical improvement,

129 R. Carbone, F. Luppi , A. Monselise, G. Bottino while administration at an equal dose has a References higher risk of causing side-effects19. Several studies have shown that long-term adminis- 1) NATIONAL HEART, LUNG, AND BLOOD INSTITUTE/NATION- tration of cromolyn/nedocromil blocks the AL INSTITUTES OF HEALTH. Global initiative for asthma. Bethesda, MD: National Heart, Lung, and Blood late phase of the allergic response, which sub- Institute/National Institutes of Health; 2002 NIH sequently heightens airway responsiveness. Publication No. 02-3659. Indeed both agents have been shown to de- 2) O’Byrne PM, Imman MD. Airway hyperrespon- crease BHR following challenge with aller- siveness. Chest 2003; 123: 411-416S. gens. Bell et al20 had observed that ne- 3) PLITMAN JD, SNAPPER JR. Nonspecific airway hy- docromil sodium and beclometasone dipropi- perresponsiveness: mechanism and meaning. onate were equally effective at reducing In: Simmons DH, Tierny DF, Eds. Current Pul- BHR but according to other studies the for- monology. St.Louis: Mosby Year Book, Inc., mer is not as effective as glucocorticoids. In 1992. contrast, in our study the combination of cro- 4) JUNIPER EF, FRITH PA, HARGREAVE FE. Airway respon- molyn and inhaled glucocorticoids was unsuc- siveness to histamine and methacholine: relation- cessful at decreasing BHR as demonstrated ship to minimum treatment to control symptoms in all subsets of pts at a 2-yr and 5-yr follow- of asthma. Thorax 1981; 36: 575-579. up. Moreover the correlation between BHR 5) MURRAY AB, FERGUSON AC, MORRISON B. Airway re- and clinical symptoms was not statistically sponsiveness to histamine as a test for overall significant at 5-yr of follow-up, and indepen- severity of asthma in children. J Allergy Clin Im- munol 1981; 68: 119-124. dent of the fact if pts were treated or not. Thus, in contrast to Sont et al17, we find that 6) AVITAL A, NOVISKI N, BAR-YISHAY E, SPRINGER C, LEVY M, GODFREY S. Nonspecific bronchial reactivity in BHR cannot be considered a marker of dis- asthmatic children depends on severity but not on ease severity in routine practice. age. Am Rev Respir Dis 1991; 144: 36-38. In order to provide valid tools for the as- 7) LARSEN GL. Asthma in children. N Engl J Med sessment of BHR and asthma it is necessary 1992; 326: 1540-1545. to develop other non-invasive markers of inflammation such as sputum induced or ex- 8) GIBSON GJ. Pathophysiology and clinical correlates of Asthma. In: Clark TJH ed. Steroids in haled air. A better knowledge of the different Asthma. Auckland, New Zealand: Adis Press mechanisms related to the regulating of BHR 1983; 11-31. and management of asthma is essential. 9) LUNDGREN R, SODERBERG M, HORSTEDT P, STENLING R. The limitation of our study lays in the fact Morphological studies of bronchial biopsies from that our population did not include asthmatic asthmatic before and after 10 years of treatment pts with severe symptoms. Including such indi- with inhaled steroids. Eur Respir J 1988; 1: 883- viduals would be difficult and ethically dis- 889. putable. Our conclusions apply therefore to pts 10) NATIONAL HEART, LUNG, AND BLOOD INSTITUTE 1995. with mild persistent asthma although further Global initiative for asthma. Global strategy for studies of large populations affected with asth- asthma management and prevention. NHLBI/ ma are necessary to confirm these findings. WHO Workshop Report. Publication N¡ 95-3695. In conclusion, BHR is caused by the inter- 11) WOOLCOCK AJ, PEAT J. What his the relationship be- action of several factors that are worth inves- tween airway hyperresponsiveness and atopy? Am J Respir Crit Care Med 2000; 161: S215- tigating and which can be grouped according S217. to their mechanism of action: (1) stimulus-en- 12) AMERICAN THORACIC SOCIETY. Standardization of hancing, (2) response-enhancing, and (3) spirometry. Am J Respir Crit Care Med 1995; stimulus and answer-enhancing. To date the 152: 1107-1136. data available relevant to each of these mech- 13) AMERICAN THORACIC SOCIETY. Guidelines for metha- anisms is partial and does not permit the ex- choline and exercise challenge testing-1999. Am clusion of either. Furthermore, a single mech- J Respir Crit Care Med 2000; 161: 309-329. anism may play a minor role in a population 14) SAS INSTITUTE INC. SAS/STAT user’s guide, version of asthmatics as a whole but may be signifi- 6. 4th Ed (vol. 2). Cary, NC. SAS, 1990; 951- 958. cant in the individual patient. BHR cannot be 15) JOSEPHS LK, GREGG I, MULLEE MA, HOLGATE ST. Non- considered a marker of disease severity in specific bronchial reactivity and its relationship to asthma and therefore is not a useful tool for the clinical expression of asthma: A longitudinal guiding asthma therapy. study. Am Rev Resp Dis 1989; 140: 350-357.

130 Bronchial hyperresponsiveness in asthmatic adults - A long-term correlation study

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